Determinants of Acute Kidney Injury in Children Undergoing Cardiopulmonary Bypass: Single-Center Experience in Saudi Arabia

Introduction Cardiopulmonary bypass (CPB) is a machine used in open cardiac surgeries and has been linked to many complications, one of which is acute kidney injury (AKI). Also, the Kidney Disease Improving Global Outcomes (KDIGO) criteria are used to diagnose AKI in the pediatric population. The study aimed to investigate the association between cardiopulmonary bypass duration and renal function impairment in pediatric patients who had cardiac surgery. Methods This was an observational, cross-sectional study conducted at the King Abdulaziz Medical City, King Faisal Cardiac Center, the section of the Pediatric Cardiac Intensive Care Unit (PICU), Ministry of National Guard Health Affairs, from January 2016 to December 2019. Patients younger than 14 years old, those having a cardiac surgery where CPB was implemented, normal pre-operative kidney functions, and having a cardiac surgery longer than 60 minutes (min) were included. The exclusion criteria were patients known to have pre-operative renal impairment and patients with pre-operative hemodynamic instability or cardiac arrest. Demographics of pre-operative, intra-operative, and post-operative data were extracted, and Statistical Package for the Social Sciences (SPSS) version 25 (Armonk, NY: IBM Corp.) was used for analysis. For descriptive statistics, frequencies and percentages for qualitative data were examined, while mean and standard deviation (SD) or median and interquartile range (IQR) quantitative data were used accordingly. Student's t-test, Mann-Whitney (median test), chi-square, or Fisher's exact tests were used for univariate analysis accordingly. Logistic regression analysis was used to determine significant predictors for developing AKI. A p-value of <0.05 would be considered significant. Results Of the 111 patients, 87 patients were included in the analysis. The median age was six months, IQR two to 13 months, body mass index (BMI) mean of 13.8, and SD 3.6. There was similar sex distribution, male 47.1% vs. female 52.9%. There were no patients in Risk Adjustment for Congenital Heart Surgery (RACHS) who scored 5 or 6. The AKI prevalence was 31% (27/87) within three days after surgery. One patient had stage 2 AKI; the rest were mild. One patient (3.7%) died. The CPB time was significantly longer in patients who developed AKI 150 (104-202), vs. non-AKI 104 (82-142) min, p=0.004. In the AKI group, the mean baseline (pre-operative) serum creatinine (sCr) was significantly lower, whereas, it was significantly higher at 24 hours (h), and 48 h post-operation (p=0.001, 0.001, and 0.036, respectively). Additionally, the estimated Glomerular Filtration Rate (eGFR) was significantly higher in the AKI group at 24 h (p=0.007). In logistical regression analysis, CPB time (per min unit time) was a significant predictor for developing AKI, OR 1.015, p=0.011 as a measured outcome. However, only CPB time >180 min was highly significant with OR 16.2, p=00.6 compared to CPB time 121-180 min OR 2.3, p=0.29 and CPB time 91-120 min OR 1.2, p=0.84. Conclusion Acute kidney injury is an expected complication of pediatric congenital heart surgery receiving CPB. Although in our single-center experience, CPB duration was a significant predictor for AKI; however, it is considered a mild complication that does not contribute significantly to short-term morbidity or mortality. A larger multicenter, national prospective data registry is recommended to explore long-term effects.


Introduction
Cardiopulmonary bypass is considered a sophisticated procedure that has become standard care in open cardiac surgeries, especially in infants and young children with congenital heart defects. Cardiopulmonary bypass enables surgeons to operate on the heart without interfering with its role. Cardiopulmonary bypass oxygenates and removes carbon dioxide from the blood, then returns it to the body through an arterial cannula with an adequate flow to maintain circulation during the surgery and provide the surgeon with a reasonably dry, bloodless surgical field [1,2].
Cardiopulmonary bypass might lead to various complications, such as renal function impairment [3], hepatic impairment [4], hyperglycemia, and systemic inflammatory response syndrome [5]. One of the most common renal function impairments that might develop is AKI, a rising complication in the pediatric population. Acute kidney injury (previously called acute renal failure) is a sudden kidney failure or kidney damage episode that happens within a few hours or days. It causes a build-up of waste products in the blood and makes it hard for the kidneys to keep the right balance of fluid in the body [6]. The incidence of AKI among pediatric patients that are between 31 days and 21 years of age who were admitted to the PICU in a single US center is 11% [7]. Several diagnostic criteria detect acute kidney injury. The most recent and modified one is the Kidney Disease Improving Global Outcomes (KDIGO) criteria which categorize the patients based on the changes in the sCr levels or urine output. In addition, AKI can be diagnosed by other biomarkers, such as eGFR and blood urea nitrogen (BUN) [8].
Few published literature have shown an association between cardiopulmonary bypass duration and renal function impairment in the pediatric population. Li et al. report an AKI incidence of 42% based on the Acute Kidney Injury Network classification system [9]. In Saudi Arabia, no published data measures the prevalence and associated risk factors of AKI post-cardiopulmonary bypass (CPB) use based on the latest KDIGO criteria. Therefore, the study aimed to measure the prevalence of AKI in pediatrics who underwent cardiac surgery for congenital heart disease requiring CPB using the KDIGO criteria, and to explore additional risk factors associated with the development of AKI, such as intensive care unit (ICU) length of stay and mechanical ventilation, and to measure the association between CPB duration and different renal function profile and morbidities.

Identification of study participants
The inclusion criteria include patients younger than 14 years old, having cardiac surgery where CPB was implemented, normal pre-op kidney functions, and having cardiac surgery lasting more than 60 min. The exclusion criteria were patients known to have pre-op renal impairment and patients with pre-operative hemodynamic instability or cardiac arrest.

Sampling technique and data collection process
Non-probability, consecutive sampling technique was used to select eligible patients. The electronic health records were screened for children admitted to the PICU who required cardiac surgery with CPB between January 2016 to December 2019. Demographics of pre-operative and post-operative data were extracted, and the inclusion and exclusion criteria were applied to find our representative sample. The variable extracted included the patient's demographics, e.g., age, weight, and height. Also, it had pre-operative, intraoperative, and post-operative characteristics and morbidities like fluid balance, the use of nephrotoxic medications, the use of angiogram, cross-clamping time, intraoperative bypass duration, use of peritoneal dialysis (PD) catheter, estimated GFR, ventilation duration, ionotropic score, renal angina index (RAI), extracorporeal membrane oxygenation (ECMO), hemoglobin, BUN, sCr levels, the central venous pressure, urine output, blood transfusion, ICU length of stay, and ventilator-free days in the ICU. Also, mortality was recorded and examined for its relation to the procedure.
Case definition: KDIGO is defined by the increase in sCr by ≥0.3 mg/dL (≥ 26.5 μmol/L) within 48 h or an increase in sCr to ≥1.5 times baseline which is known or presumed to have occurred within the previous 7 days, or urine volume <0.5 mL/kg/h for 6 h [8]. Further definitions for the severity of AKI are shown in Appendix 1, and other variable definitions are in Appendix 2.

Data analysis
An online statistical software, OpenEpi [10], was used to calculate the sample size based on a previous study [9] that estimated a difference of 30% of patients who are exposed to pronged CPB time and developed AKI (51%) compared to unexposed (21%). The ratio of unexposed/exposed is 2:1, the calculated sample size in exposed is 29, the sample size unexposed is 57, and the total is 86. Such a sample is needed to detect a statistical significance difference assuming a significance level of 95% and a power (1-beta) of 80%, We used Microsoft Excel files to manage the data, and we will then transfer them to Statistical Package for the Social Sciences (SPSS) version 25 for analysis. For descriptive statistics, frequencies and percentages for qualitative data were examined. At the same time, mean and standard deviation (SD) or median and interquartile range (IQR) will be produced for quantitative data in normally distributed or skewed data, respectively. Student t-test was used for comparing two groups for normally distributed data, and the Mann-Whitney test (median test) for skewed data. Chi-square or Fisher exact test was used to comparing between categorical data. Logistic regression analysis was used to determine significant predictors for developing AKI. Collinearity was assessed, and those with high correlation (r>0.45) were eliminated from the model. The model adjusted for age, gender, and body mass index (BMI). It included CBP time, Risk Adjustment in Congenital Heart Surgery (RACHS) score (score of 2 as reference), RAI (score of 5 as reference), and baseline creatinine as independent variables. A P-value of <0.05 would be considered significant.

Results
We studied 111 children who underwent heart surgery for congenital defects between January 1, 2016, and December 31, 2019. Of the 111 patients, 14 were excluded from the analysis because their cardiac surgery duration was less than 60 min or they were hemodynamically unstable and known to have pre-operative renal impairment. Another 10 patients were excluded because they had missing data or incomplete medical records. Hence 87 patients were included in the analysis. The median age was six months, IQR two to 13 months, BMI mean of 13.8, and SD 3.6. There was similar sex distribution, male 47.1% vs. female 52.9%. There were no patients in RACHS who scored 5 or 6.
Furthermore, we screened for acute kidney injury according to the KDIGO criteria (case definition of AKI in Appendix 1) and ended up with 27 patients who met the criteria-making (further details are shown in Appendix 3); the AKI prevalence in our population of 31% within three days after surgery ( Figure 1).

FIGURE 1: Flow chart for patient recruitment.
PICU: pediatrics intensive care unit; CPB: cardiopulmonary bypass; AKI: acute kidney injury There was a stepwise increase of AKI prevalence with the rise of CPB time, where four patients (15%) had a CPB time of 61-90 min, seven (26%) had 91-120 min, seven (26%) had 121-180 min, and nine patients (33%) had a CPB time of equal to or more than 180, Fisher's exact p=0.007, and Spearman correlation 0.34, p=0.001 ( Figure 2). Interestingly only one patient had a moderate case of AKI, stage 2; the rest were mild. In addition, one out of the 27 patients was a death case, making our cohort's mortality rate (3.7%).

Discussion
This single tertiary center study showed an association between cardiopulmonary bypass duration and the deterioration of renal function in children post-cardiac surgery. The prevalence of AKI (31%) according to the KDIGO criteria. Our prevalence is lower than previously reported by Li et al. and Aydin et al., who had 42% and 51%, respectively [9,11]. Our sample's characteristics were comparable with the multicenter study of Li et al. apart from the smaller age group; however, their sample was collected more than a decade ago. Their study established a benchmark for AKI prevalence in children post-cardiac surgery for congenital heart disease [9].
Cardiopulmonary bypass is the mainstay management in open heart surgeries as a replacement for the heart, oxygenating and removing carbon dioxide from the blood, then returning it to the body through an arterial cannula with adequate flow to maintain the circulation during the time of the surgery [2]. Although the pathophysiology is still unclear, CPB was linked to renal vasoconstriction and redirection of the blood away from the kidney, which, if merged with hemodilution, decreases renal oxygen delivery by 20% during the surgery. On the other hand, renal demand for oxygen is unchanged. This mismatch in renal oxygenation is accompanied by a release of a tubular injury marker that further aggravates renal functions after weaning from CPB [3].
Many studies have examined that the associated time of the CPB may be considered a risk factor for developing kidney insult in adults [12] and only a few children; our study adds to the body of literature this association in young children [13]. Moreover, there was a stepwise increase in AKI with each 30 min increase in CPB time beyond 60 min. The most pronounced was CPB time of >180 min, with 16 times the odds of developing AKI even after adjusting for modifiable factors. This association was consistent with the literature, which found a stepwise increasing risk for developing AKI with longer durations of CPB, with the highest incidence at >180 min [9].
We explored the association between the Renal Angina Index score and AKI, which is used as a predictive tool to calculate the risk of developing AKI upon ICU admission, results in univariate and regression analysis didn't find an association. To our knowledge, we didn't see a study that examined such an association. Preoperative baseline creatinine was lower in the group of patients who developed AKI. However, this was most likely due to expected age-associated lower creatinine values, which is evidenced by the fact that the baseline estimated glomerular filtration rates were not statistically different between the AKI and non-AKI groups [9]. In our study, only two patients had been put on ECMO, and only one died in the AKI group [14]. Our study is the first to analyze the association between CBP time and AKI in children undergoing heart surgery for congenital heart disease in Saudi Arabia. It also was the first to examine the association between renal angina score and AKI. On the other hand, our study did not include patients with RACHS-1 because they were all simple procedures and ended up with a CPB time of less than 60 min [15]. In addition, our study was limited by being conducted in one center compared to their multicenter cohort by Li et al., they included patients up to 17 years of age, also included patients who had a duration of CPB less than 60 min, while in our cohort we had to exclude anyone older than 14 years old. However, our results did not differ [9].
We recommend having a larger national multicenter prospective study to elaborate more on further modifiable risk factors in our population such as maternal antenatal risk [16] and multidomain socioeconomic risk score [17]. Long-term follow-up is also recommended to explore the effect on neurodevelopment [18,19], healthcare utilization, growth, renal function, and possibly adulthood complications [20]. Further studies are needed for the renal function analysis to clarify the long-term followup.

Conclusions
Acute kidney injury is an expected complication of pediatric congenital heart surgery receiving CPB. Although in our single-center experience, CPB duration was a significant predictor for AKI; however, it is considered a mild complication that does not contribute significantly to short-term morbidity or mortality. a larger multicenter, national prospective data registry is recommended to explore long-term effects.   International Medical Research Center IRB Office issued approval #IRBC/0883/19. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.